The skeleton is a common metastatic site. The interaction between cancer cells and bone results in unique interactions. In the case of prostate cancer (CAP) metastases, these interactions include a combination of osteolytic and osteoblastic activity that creates a significant challenge to understanding the biology of CaP skeletal metastases. Many cancers, including CaP, induce angiogenesis through vascular endothelial growth factor (VEGF). Recently, VEGF has been demonstrated to mediate bone remodeling. Specifically, VEGF indirectly supports bone resorption through promoting angiogenesis and recruitment of osteoclasts. Additionally, VEGF promotes bone production through direct activation of osteoblast differentiation. Thus, the overall activity of VEGF is to promote bone turnover. In the current proposal, we present data that CaP cells promote both osteoclastogenesis and osteoblast differentiation through VEGF in vitro. These observations, together with the previous reports that VEGF CaP cell metastases promote bone remodeling, in part, through VEGF. To test this hypothesis, we will perform the following specific aims 1. Determine if VEGF plays an early and/or late role in the development of CaP bone metastases. We will examine temporal expression of VEGF during CaP skeletal tumor development in a SCID-human bone model including in vivo bioluminescent imaging of VEGF promoter activity. We will also block VEGF activity in this model to determine VEGF's functional role in CaP-mediated osteosclerosis. 2. Test if CaP-mediated VEGF activity promotes osteoblastic activity independent of its ability to promote osteolytic activity in vivo. We will block osteoclast activation, with osteoprotegerin, at early and late development stages of CaP skeletal tumor development and determine effects on bone and tumor. 3. Determine the mechanism through which VEGF accounts for prostate cancer-induced osteoblastic activity. In this aim, we will test which VEGF isoform contributes to CaP cells' osteoblastic activity. We will also evaluate if VEGF induces this activity through MAPK.